What are the common causes of anemia during pregnancy. How is anemia diagnosed in pregnant women. What are the risks associated with anemia in pregnancy. How is anemia treated during pregnancy.

Understanding Anemia in Pregnancy: Prevalence and Physiological Changes

Anemia is a common condition that affects up to one-third of women during the third trimester of pregnancy. To understand why this occurs, it’s important to examine the physiological changes that take place during pregnancy.

During pregnancy, the body undergoes significant changes in blood composition:

• Erythroid hyperplasia of the bone marrow occurs
• Red blood cell (RBC) mass increases
• Plasma volume increases disproportionately, leading to hemodilution

This hemodilution, also known as hydremia of pregnancy, results in a decrease in hematocrit (Hct) levels. In healthy non-pregnant women, the Hct ranges between 38% and 45%. However, during pregnancy, these levels drop to about 34% in late single pregnancies and 30% in late multifetal pregnancies.

Defining Anemia in Pregnancy

How is anemia defined during pregnancy? The classification of anemia is based on hemoglobin (Hb) and hematocrit (Hct) levels, which vary by trimester:

• 1st trimester: Hb < 11 g/dL or Hct < 33%
• 2nd trimester: Hb < 10.5 g/dL or Hct < 32%
• 3rd trimester: Hb < 11 g/dL or Hct < 33%

If hemoglobin levels fall below 9 g/dL at any point during pregnancy, it is considered severe anemia and requires immediate attention.

Common Causes of Anemia During Pregnancy

What are the primary causes of anemia in pregnant women? The most prevalent causes include:

1. Iron deficiency
2. Folate deficiency

Iron deficiency anemia accounts for approximately 95% of anemia cases during pregnancy. This type of anemia can result from:

• Inadequate dietary intake, especially in adolescent girls
• A previous pregnancy
• Normal recurrent loss of iron in menstrual blood before pregnancy

Folate deficiency is another common cause of anemia during pregnancy. This can occur due to increased folic acid requirements during pregnancy or inadequate dietary intake.

Diagnosis of Anemia in Pregnancy

How do healthcare providers diagnose anemia in pregnant women? The diagnostic process typically begins with a complete blood count (CBC). Based on the results, further testing may be required:

For Microcytic Anemias (MCV < 80 fL)

If the mean corpuscular volume (MCV) is low, indicating microcytic anemia, the evaluation includes:

• Testing for iron deficiency by measuring serum ferritin levels
• Screening for hemoglobinopathies using hemoglobin electrophoresis

For Macrocytic Anemias (MCV > 100 fL)

In cases of macrocytic anemia, where the MCV is high, the evaluation focuses on:

• Measuring serum folate levels
• Assessing vitamin B12 levels

For Mixed Cause Anemias

When anemia appears to have multiple causes, a comprehensive evaluation incorporating tests for both microcytic and macrocytic anemias is necessary.

Risks Associated with Anemia in Pregnancy

Why is it crucial to address anemia during pregnancy? Anemia can lead to several complications for both the mother and the developing fetus:

• Increased risk of preterm delivery
• Low birth weight
• Higher likelihood of postpartum maternal infections

Moreover, severe anemia can cause symptoms such as fatigue, weakness, light-headedness, and mild dyspnea during exertion. In more severe cases, it may lead to tachycardia or hypotension.

Treatment Approaches for Anemia in Pregnancy

How is anemia treated during pregnancy? The treatment approach depends on the underlying cause and severity of the anemia:

Iron Deficiency Anemia

For iron deficiency anemia, which is the most common type, treatment typically involves iron supplementation:

• One 325-mg ferrous sulfate tablet taken midmorning is usually effective
• Higher or more frequent doses may increase gastrointestinal side effects

Folate Deficiency Anemia

In cases of folate deficiency, folic acid supplementation is recommended. This is often included in prenatal vitamins, but additional supplementation may be necessary in some cases.

Severe Anemia

For severe anemia or cases with significant symptoms, more aggressive treatment may be required:

• Blood transfusion may be indicated if severe constitutional symptoms (e.g., light-headedness, weakness, fatigue) or cardiopulmonary symptoms (e.g., dyspnea, tachycardia, tachypnea) are present
• The decision to transfuse is based on symptoms rather than hematocrit levels alone

Special Considerations in Anemia Management During Pregnancy

Are there any special cases that require particular attention in anemia management during pregnancy? Indeed, certain situations call for specialized care:

Jehovah’s Witness Patients

Pregnant women who are Jehovah’s Witnesses present a unique challenge, as they are likely to refuse blood transfusions. In these cases:

• Obstetricians should consult with a perinatologist as early as possible
• Alternative treatments and management strategies need to be considered and discussed with the patient

Hemoglobinopathies

Women with hemoglobinopathies, such as sickle cell disease or thalassemia, require specialized care and monitoring throughout pregnancy. These conditions can complicate anemia management and may require input from a hematologist.

Preventive Measures and Nutritional Considerations

How can anemia be prevented or minimized during pregnancy? Several preventive measures and nutritional considerations can help maintain healthy hemoglobin levels:

Dietary Iron Intake

Encouraging a diet rich in iron-containing foods can help prevent iron deficiency anemia. Good sources of iron include:

• Lean red meat
• Poultry
• Fish
• Beans and lentils
• Fortified cereals
• Dark leafy greens

Prenatal Vitamins

Most prenatal vitamins contain iron and folic acid, which can help prevent both iron and folate deficiency anemias. Healthcare providers often recommend starting these supplements even before conception.

Vitamin C Intake

Vitamin C enhances iron absorption. Encouraging the consumption of vitamin C-rich foods alongside iron-rich foods or supplements can improve iron uptake.

Regular Prenatal Check-ups

Regular prenatal check-ups allow for early detection and management of anemia. Routine blood tests can identify anemia before it becomes severe.

Monitoring and Follow-up Care for Anemic Pregnant Women

How should anemic pregnant women be monitored and followed up? Proper monitoring and follow-up care are crucial for managing anemia effectively during pregnancy:

Regular Blood Tests

Periodic blood tests should be conducted to monitor hemoglobin and hematocrit levels. The frequency of these tests may increase if anemia is diagnosed.

Assessing Treatment Response

For women receiving treatment for anemia, follow-up tests are essential to evaluate the effectiveness of the intervention. This may include:

• Retesting hemoglobin and hematocrit levels
• Monitoring serum ferritin levels in cases of iron deficiency anemia
• Assessing folate levels in cases of folate deficiency

Adjusting Treatment as Needed

Based on the response to treatment, healthcare providers may need to adjust the dosage or type of supplementation. In some cases, alternative treatments may be considered if the initial approach is ineffective.

Postpartum Follow-up

Anemia management doesn’t end with delivery. Postpartum follow-up is important to ensure that hemoglobin levels return to normal and to address any ongoing nutritional deficiencies.

Impact of Anemia on Labor and Delivery

How does anemia affect labor and delivery? Anemia can have several implications for the birthing process:

Increased Risk of Complications

Anemic women may face a higher risk of complications during labor and delivery, including:

• Increased likelihood of cesarean section
• Higher risk of postpartum hemorrhage
• Greater chance of needing a blood transfusion during or after delivery

Reduced Stamina

Anemia can lead to fatigue and reduced stamina, which may affect a woman’s ability to cope with the physical demands of labor.

Fetal Distress

Severe anemia may impact the oxygen supply to the fetus, potentially leading to fetal distress during labor.

Postpartum Recovery

Anemic women may experience a slower postpartum recovery, with increased fatigue and a higher risk of postpartum depression.

Given these potential complications, it’s crucial to address anemia before labor begins whenever possible. This may involve more aggressive treatment in the weeks leading up to the due date.

Long-term Effects of Anemia in Pregnancy

What are the potential long-term effects of anemia during pregnancy? While many effects of anemia are immediate, some can have longer-lasting implications:

Maternal Health

For the mother, untreated anemia during pregnancy can lead to:

• Chronic fatigue and reduced quality of life
• Increased susceptibility to infections
• Higher risk of developing postpartum depression

Infant Health

For the infant, maternal anemia can have several long-term effects:

• Increased risk of developmental delays
• Higher likelihood of cognitive impairments
• Greater susceptibility to childhood anemia

Future Pregnancies

Women who experience anemia in one pregnancy are at higher risk of developing anemia in subsequent pregnancies. This underscores the importance of addressing nutritional deficiencies and maintaining good health between pregnancies.

Breastfeeding

Anemia can affect a mother’s ability to produce adequate breast milk, potentially impacting the nutritional status of the newborn.

Given these potential long-term effects, it’s crucial to view anemia management as part of a broader strategy for promoting maternal and child health, extending beyond the immediate pregnancy and postpartum period.

Emerging Research and Future Directions in Anemia Management During Pregnancy

What new developments are on the horizon for managing anemia in pregnancy? Several areas of research show promise for improving anemia detection and treatment:

Novel Iron Formulations

Researchers are exploring new iron formulations that may be better tolerated and more effectively absorbed. These include:

• Nanoparticle-based iron supplements
• Iron-fortified foods specifically designed for pregnant women
• Novel oral iron preparations with reduced gastrointestinal side effects

Genetic Testing

Advances in genetic testing may allow for early identification of women at higher risk for developing anemia during pregnancy. This could enable more targeted prevention strategies.

Non-invasive Hemoglobin Monitoring

New technologies for non-invasive hemoglobin monitoring are being developed. These could allow for more frequent and convenient anemia screening during pregnancy.

Personalized Nutrition Plans

Research into personalized nutrition based on genetic profiles and individual health status may lead to more effective strategies for preventing and treating anemia during pregnancy.

Microbiome Research

Emerging research on the gut microbiome may provide new insights into iron absorption and metabolism, potentially leading to novel approaches for anemia prevention and treatment.

These research directions hold promise for improving anemia management in pregnancy, potentially leading to better outcomes for both mothers and infants. As new findings emerge, clinical guidelines for anemia management during pregnancy may evolve to incorporate these advancements.

Anemia in Pregnancy – Gynecology and Obstetrics

By

Lara A. Friel

, MD, PhD, University of Texas Health Medical School at Houston, McGovern Medical School

Reviewed/Revised Oct 2021 | Modified Sep 2022

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Normally during pregnancy, erythroid hyperplasia of the marrow occurs, and red blood cell (RBC) mass increases. However, a disproportionate increase in plasma volume results in hemodilution (hydremia of pregnancy): hematocrit (Hct) decreases from between 38% and 45% in healthy women who are not pregnant to about 34% during late single pregnancy and to 30% during late multifetal pregnancy. The following hemoglobin (Hb) and Hct levels are classified as anemic:

• 1st trimester: Hb

• 2nd trimester: Hb

• 3rd trimester: Hb

If Hb is

Anemia Red Blood Cell Production Red blood cell (RBC) production (erythropoiesis) takes place in the bone marrow under the control of the hormone erythropoietin (EPO). Juxtaglomerular cells in the kidney produce erythropoietin… read more occurs in up to one third of women during the 3rd trimester. The most common causes are

• Iron deficiency Iron Deficiency Iron (Fe) is a component of hemoglobin, myoglobin, and many enzymes in the body. Heme iron is contained mainly in animal products. It is absorbed much better than nonheme iron (eg, in plants… read more

• Folate deficiency Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin… read more

Obstetricians, in consultation with a perinatologist, should evaluate anemia in pregnant Jehovah’s Witness patients (who are likely to refuse blood transfusions) as soon as possible.

Early symptoms of anemia are usually nonexistent or nonspecific (eg, fatigue, weakness, light-headedness, mild dyspnea during exertion). Other symptoms and signs may include pallor and, if anemia is severe, tachycardia or hypotension.

Anemia increases risk of

• Preterm delivery Preterm Labor Labor (contractions resulting in cervical change) that begins before 37 weeks gestation is considered preterm. Risk factors include prelabor rupture of membranes, uterine abnormalities, infection… read more

• Low birth weight

• Postpartum maternal infections

Diagnosis of anemia begins with CBC; usually, if women have anemia, subsequent testing is based on whether the MCV is low ( 100 fL):

• For microcytic anemias: Evaluation includes testing for iron deficiency (measuring serum ferritin) and hemoglobinopathies Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span. .. read more (using hemoglobin electrophoresis). If these tests are nondiagnostic and there is no response to empiric treatment, consultation with a hematologist is usually warranted.

• For macrocytic anemias: Evaluation includes serum folate and vitamin B12 levels.

• For anemia with mixed causes: Evaluation for both types is required.

Treatment of anemia during pregnancy is directed at reversing the anemia (see below).

Transfusion is usually indicated for any anemia if severe constitutional symptoms (eg, light-headedness, weakness, fatigue) or cardiopulmonary symptoms or signs (eg, dyspnea, tachycardia, tachypnea) are present; the decision is not based on the Hct.

Pearls & Pitfalls

• Hemodilution occurs during pregnancy, but oxygen-carrying capacity remains normal throughout pregnancy.

• The most common causes of anemia during pregnancy are iron deficiency and folate acid deficiency.

• Anemia increases risk of preterm delivery and postpartum maternal infections.

• If Hb is

• Treat the cause of the anemia if possible, but if patients have severe symptoms, transfusion is usually indicated.

About 95% of anemia cases during pregnancy are iron deficiency anemia Iron Deficiency Anemia Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as occurs in celiac disease, is a much less common cause. Symptoms are usually nonspecific… read more . The cause is usually

• Inadequate dietary intake (especially in adolescent girls)

• A previous pregnancy

• The normal recurrent loss of iron in menstrual blood (which approximates the amount normally ingested each month and thus prevents iron stores from building up) before the woman became pregnant

Typically, Hct is ≤ 30%, and MCV is

One 325-mg ferrous sulfate tablet taken midmorning is usually effective. Higher or more frequent doses increase GI adverse effects, especially constipation, and one dose blocks absorption of the next dose, thereby reducing percentage intake.

About 20% of pregnant women do not absorb enough supplemental oral iron; a few of them require parenteral therapy. The iron deficit may be calculated, and the iron can often be replaced over one or two infusions. Hct or Hb is measured weekly to determine response. If iron supplements are ineffective, concomitant folate deficiency should be suspected.

Neonates of mothers with iron deficiency anemia usually have a normal Hct but decreased total iron stores and a need for early dietary iron supplements.

Although the practice is controversial, iron supplements (usually ferrous sulfate 325 mg orally once a day) are usually given routinely to pregnant women to prevent depletion of body iron stores and prevent the anemia that may result from abnormal bleeding or a subsequent pregnancy.

Folate deficiency Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin… read more increases risk of neural tube defects Overview of Congenital Neurologic Anomalies Congenital brain anomalies cause a spectrum of neurologic deficits; although some may be barely noticeable, others may be fatal. Some of the most serious neurologic anomalies (eg, anencephaly… read more and possibly fetal alcohol syndrome Fetal Alcohol Syndrome Alcohol exposure in utero increases the risk of spontaneous abortion, decreases birth weight, and can cause fetal alcohol syndrome, a constellation of variable physical and cognitive abnormalities… read more . Deficiency occurs in 0.5 to 1.5% of pregnant women; megaloblastic macrocytic anemia Megaloblastic Macrocytic Anemias Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly red blood cells. Diagnosis is usually based… read more is present if deficiency is moderate or severe.

Rarely, severe anemia and glossitis occur.

Folate deficiency is suspected if CBC shows anemia with macrocytic indices or high RBC distribution width (RDW). Low serum folate levels confirm the diagnosis.

Treatment is folic acid 1 mg orally twice a day.

Severe megaloblastic anemia may warrant bone marrow examination and further treatment in a hospital.

For prevention, all pregnant women and women who are trying to conceive are given folic acid 0.4 to 0.8 mg orally once a day. Women who have had a fetus with spina bifida should take 4 mg once a day, starting before conception.

During pregnancy, hemoglobinopathies, particularly sickle cell disease Sickle Cell Disease Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in people with African ancestry. It is caused by homozygous inheritance of genes for hemoglobin. .. read more , Hb S-C disease Hemoglobin S-C Disease Hemoglobin S-C disease is a hemoglobinopathy that causes symptoms similar to those of sickle cell disease, but usually less severe. (See also Overview of Hemolytic Anemia.) The heterozygous… read more , and beta- and alpha- thalassemia Thalassemias Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha-thalassemia is particularly common among people with African, Mediterranean… read more , can worsen maternal and perinatal outcomes. Genetic screening genetic screening Genetic Screening for Some Ethnic Groups for some of these disorders is available.

Preexisting sickle cell disease, particularly if severe, increases risk of the following:

• Maternal infection (most often, pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and… read more , urinary tract infections [UTIs] Postpartum Pyelonephritis Pyelonephritis is bacterial infection of the renal parenchyma. Pyelonephritis may occur postpartum if bacteria ascend from the bladder. The infection may begin as asymptomatic bacteriuria during… read more , and endometritis Postpartum Endometritis Postpartum endometritis is uterine infection, typically caused by bacteria ascending from the lower genital or gastrointestinal tract. Symptoms are uterine tenderness, abdominal or pelvic pain… read more )

• Pregnancy-induced hypertension Hypertension in Pregnancy Recommendations regarding classification, diagnosis, and management of hypertensive disorders (including preeclampsia) are available from the American College of Obstetricians and Gynecologists… read more

• Heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal… read more

• Pulmonary infarction Pathophysiology

• Fetal growth restriction Small-for-Gestational-Age (SGA) Infant Infants whose weight is < the 10th percentile for gestational age are classified as small for gestational age. Complications include perinatal asphyxia, meconium aspiration, polycythemia… read more

• Preterm delivery Preterm Labor Labor (contractions resulting in cervical change) that begins before 37 weeks gestation is considered preterm. Risk factors include prelabor rupture of membranes, uterine abnormalities, infection… read more

• Low birth weight Small-for-Gestational-Age (SGA) Infant Infants whose weight is < the 10th percentile for gestational age are classified as small for gestational age. Complications include perinatal asphyxia, meconium aspiration, polycythemia. .. read more

Anemia almost always becomes more severe as pregnancy progresses. Sickle cell trait increases the risk of UTIs but is not associated with severe pregnancy-related complications.

Treatment of sickle cell disease during pregnancy is complex. Painful crises should be treated aggressively. Prophylactic exchange transfusions to keep Hb A at ≥ 60% reduce risk of hemolytic crises and pulmonary complications, but they are not routinely recommended because they increase risk of transfusion reactions, hepatitis, HIV transmission, and blood group isoimmunization. Prophylactic transfusion does not appear to decrease perinatal risk. Therapeutic transfusion is indicated for the following:

• Symptomatic anemia

• Heart failure

• Severe bacterial infection

• Severe complications of labor and delivery (eg, bleeding, sepsis)

Hb S-C disease may first cause symptoms during pregnancy. The disease increases risk of pulmonary infarction by occasionally causing bony spicule embolization. Effects on the fetus are uncommon but, if they occur, often include fetal growth restriction.

Sickle cell–beta-thalassemia is similar to Hb S-C disease but is less common and more benign.

Alpha-thalassemia does not cause maternal morbidity, but if the fetus is homozygous, hydrops and fetal death occur during the 2nd or early 3rd trimester.

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The relationship of hemoglobin and hematocrit in the first and second half of pregnancy with pregnancy outcome

Iran J Nurs Midwifery Res. 2012 Feb; 17(2 Suppl1): S165–S170.

, MSc,^{1, MSc,2 and , MSc3}

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Background:

Considering the relationship of low and high levels of hemoglobin and hematocrit with some pregnancy complications, we decided to study their relationship with pregnancy outcome. This study also aimed to investigate the changes in hemoglobin and hematocrit values during the second and first half of pregnancy and its relationship with pregnancy outcome.

Materials and Methods:

In a prospective cohort study, 520 Iranian pregnant women, aged 15 to 45 years that were supported by health centers in Isfahan, Iran, were recruited using quota sampling method. Exclusion criteria comprised of 36 conditions that were related to the maternal and infant outcomes. Hemoglobin and hematocrit were measured in eligible mothers during the 6^th-11^th weeks and 26^th-30^th weeks of pregnancy. They were monitored until delivery and the data regarding their pregnancy outcome were collected.

Findings:

Low levels of hemoglobin during the first half of pregnancy was associated with preeclampsia (p = 0.024). Moreover, low levels of hemoglobin during the second half of pregnancy was associated with the risk of preterm premature rupture of membranes (p = 0.01). In addition, mothers with lower blood dilution, as a physiological process during pregnancy, were more prone to preeclampsia (p = 0.04).

Conclusions:

Hemoglobin levels in the first and second half of pregnancy can predict preeclampsia and premature preterm rupture of membranes. Increased hematocrit levels in the second half of pregnancy or lack of reduction of hematocrit levels in the second half compared to the first half can estimate preeclampsia.

Keywords: Hemoglobin, hematocrit, pregnancy outcome

In the past three decades, the relationship between maternal hemoglobin and hematocrit levels and pregnancy outcome has been generally studied. Maternal anemia has been considered as a risk factor for an undesirable pregnancy outcome.[1–3] On the other hand, the relationship between high levels of hemoglobin and hematocrit and the complications such as preterm delivery, low birth weight, intrauterine growth restriction and intrauterine fetal death have been also shown in several studies.[4–7] According to the study of Stove et al. conducted on Bulgarian pregnant women, increase of hematocrit, hemoglobin and red cell mass in early pregnancy can be considered a risk factor for preeclampsia, intrauterine growth restriction and fetal death in the later stages of pregnancy.[8]

Measuring hemoglobin and hematocrit is common during pregnancy. Normal level of hemoglobin is 12 to 16 grams per deciliter for women of childbearing age. Its minimum normal value is 11 grams per deciliter in the first and third trimester of the pregnancy and 10.5 grams per deciliter in the second trimester. Its amount gets lower than normal due to anemia and higher than normal because of erythrocytosis. Normal values of hematocrit have been determined from 36 to 48 percent for women in childbearing age. The cause of its decrease in adults and during pregnancy is anemia, and the reasons for its increase are myeloproliferative disorders, chronic obstructive pulmonary disease and other hypoxic lung conditions.

Both hemoglobin and hematocrit are measured through fresh whole blood and are dependent on plasma volume. Thus, factors such as dehydration as well as overhydration can affect the test results.[9] In fact, hematocrit is a more precise parameter than hemoglobin to determine the ratio of erythrocyte volume to the total blood volume.[10] Viscosity of blood is changeable, which is associated with geometry of blood vessels and blood flow level, blood plasma concentration, volume concentration of blood cells and hematocrit. Therefore, change in the mentioned parameters can be a warning of a high-risk pregnancy.[11] The relationship between ferritin level and pregnancy outcome as well as the relationship between the hematocrit levels provide grounds for more investigation especially considering that such a study has not yet been done in Iran.[12,13] Our purposes were to examine the relationship of hemoglobin and hematocrit during the first and second half of pregnancy with pregnancy outcome including premature rupture of membranes (PROM) before the onset of labor, preterm premature rupture of membranes (PPROM) before completion of the thirty-seventh week of pregnancy, preeclampsia, delivery type and birth anthropometric indicators. We also aimed to study the changes in hemoglobin and hematocrit values during the second half of pregnancy compared to the first half and its relationship with pregnancy outcome.

In a prospective cohort study that was conducted on 520 pregnant women, the data were collected in three stages. Sampled population was Iranian women aged 15- 49 years covered by health centers whose delivery in hospital led to the birth of alive and apparently healthy baby. Subjects were selected from different centers through quota sampling method. Considering the possibility of loss to follow up and exclusion of the subjects whose babies suffered from abnormality, intrauterine fetal death and newborn death, a larger sample size (about 50) was determined. Exclusion criteria (36 items) were conditions and states that affect pregnancy outcome. These condition included causes of preterm delivery, low birth weight, preeclampsia, premature rupture of membranes, preterm premature rupture of membranes, smoking, drug addiction, digestive disorders, hemoglobinopathies, nutritional diseases, allergies and mental disorders. To determine the mentioned criteria, the results of the routine tests during pregnancy as well as the result obtained by the medical examination of the physician and the recommendation of the specialist in necessary cases were used. Pregnant women with gestational age of 6 weeks or less were interviewed in their first visit for prenatal care and in case they were eligible and willing to participate in the study, they were recruited. The participants were referred to the laboratory during the 6^th– 11^th and 26^th-30^th weeks of gestational age and their hemoglobin and hematocrit were measured. It should be noted that 96 percent of the subjects took iron and folic acid pills. However, in order to increase the confidence in the study, all patients were referred to the same laboratory and all the samples were evaluated by the same technician. Further, the subjects were monitored until the delivery and the data regarding their pregnancy outcome were collected through birth files, prenatal care files and phone calls. Data collection tool was questionnaires which were completed through interviews with eligible mothers either in person or by phone call. Content validity of the questionnaire was confirmed by experts. The data in the prenatal care and delivery files which had been completed by midwives, obstetricians, and neonatologists were used to determine the reliability of the questionnaire. Student’s t-test, Pearson correlation test and regression analysis was used to analyze the data through SPSS software version 18. Numerical values were represented as mean (standard deviation).

Pregnant women were at 15–41 years age group and their education was at the secondary level in 45.7 percent of cases and about 60 percent of pregnant women were experiencing their first pregnancy. Hemoglobin in the first half of pregnancy was 12.61 (1.06) g/dL and average hematocrit in the first half of pregnancy was 38.19 (3.07) grams percent. Hemoglobin in the second half of pregnancy was 11.91 (1.02) g/dL and average hematocrit was 36.28 (2.81) g/dl. Minimum and maximum amounts of hemoglobin were 7.4 and 16.1 g/dL in the first half and 7 and 15 g/dL in the second half, respectively. Moreover, the minimum and maximum values of hematocrit in the first half were calculatedas 26 and 48. 7 percent and in the second half as 27 and 46 percent, respectively. The average hemoglobin and hematocrit in two halves of pregnancy in women who were affected with premature rupture of membranes (before the onset of labor and after 37 weeks) were not different with other mothers. Furthermore, there was no statistically significant difference in the average hemoglobin and hematocrit in two halves of pregnancy between those who had vaginal delivery and cesarean section (). Moreover, no relationship was found between hemoglobin in two halves of pregnancy and birth anthropometric indices (p > 0.05).

Table 1

The comparison of average hemoglobin and hematocrit in the first and second half of pregnancy outcome

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In the present study, about 2.35 percent of participants affected with preterm premature rupture of membranes and the average hemoglobin in the first and average hematocrit in the second half did not differ in both groups. However, the average hemoglobin in the second half of pregnancy of the group who later developed preterm premature rupture of membranes was significantly lower than others (p = 0. 01). About 4 percent of subjects had signs and symptoms of preeclampsia. Average hemoglobin in the first half of pregnancy of these women was significantly more than that of others (p = 0.024) (). Significant inverse relationship of hematocrit in the second half with height (p = 0.024 and r = -0.093) and weight (p = 0.03 and r = -0.095) at birth was seen, so that the increase of hematocrit in the second half of pregnancy, correlated with decreased birth weight and height, but no significant relationship was found between head circumference at birth, and hemoglobin or hematocrit in the two halves (p > 0.05). Since the most important factor associated with indices of weight, height and head circumference at birth is gestational age, mentioned variables will be also influenced by some variables such as mother’s age, education and body mass index, the number of pregnancies and household income. The relationship of hematocrit in the second half with birth weight and height was examined through a more accurate test using regression analysis while household income, mother’s education and age, gestational age, maternal body mass index before pregnancy and the number of pregnancies were included in the model. No statistically significant relationship was found between hematocrit in the second half and birth weight and height (p = 0.181 and p = 0.244, respectively). But a significant relationship was found between gestational age (p < 0.001), mother’s body mass index (p = 0.001), and education (p = 0.021), and birth weight. Moreover, a significant correlation was found between gestational age (p < 0.001), mothers’ age (p = 0.01), mothers’ education (p < 0.001), and birth height. In addition, gestational age (p < 0.001), maternal age (p = 0.01), and mother’s education (p < 0.001) were significantly associated with head circumference at birth. Thus, among the mentioned variables, gestational age was strongly associated with the three infant anthropometric indices (p < 0.001).

To study the changes in hemoglobin and hematocrit values in the second half of pregnancy compared to the first half, the difference between hemoglobin and hematocrit in the two halves of pregnancy was determined for all of mothers. In 381 (72.9%) mothers, hemoglobin and hematocrit levels in the second half of pregnancy decreased to the first half of pregnancy and in 141 (27.0%), the difference between hematocrit in the two halves of pregnancy was zero or higher. In the next step, the relationship of the difference between hemoglobin and hematocrit in the two halves of pregnancy was assessed with premature rupture of membranes and preterm premature rupture of membranes, delivery type, preeclampsia, and gestational age. The difference between hematocrit in the two halves was inversely associated with gestational age (p = 0.006, r = -0.21). In addition, no significant relationship was found in terms of the hematocrit and hemoglobin differences in the two halves of pregnancy with premature rupture of membranes, preterm premature rupture of membranes and delivery type (p > 0.05). However, the difference between hematocrit in the two halves of pregnancy was significantly less in those who were diagnosed with preeclampsia than other mothers (p = 0. 04), which means hematocrit in the second half of pregnancy in these people has been more than others.

In this study, the average hemoglobin in the second half was significantly lower in the group who later suffered from preterm premature rupture of membranes than other mothers. Ferguson et al. also showed that premature rupture of membranes before 37 weeks was significantly more in women with hemoglobin below 11 g/dl than others. They believed that low levels of hemoglobin may be a sign of a concealed infection.[14] In their study, Zhang et al. also discovered a relationship between low levels of hemoglobin and increase in the risk of preterm premature rupture of membranes later in pregnancy.[15] From the viewpoint of these researchers, low levels of hemoglobin (anemia) early in pregnancy or during pregnancy, which is caused either by previous anemia or the anemia occurred during pregnancy can predispose the mother to infections, hypoxia or oxidative stress and thereby lead to preterm delivery. The proposed explanation for this relationship was the lower socioeconomic and nutritional condition in these mothers.[16] Additionally, our data suggested that hemoglobin in the first half was significantly lower in women who developed preeclampsia. Through the study conducted on 162 pregnant mothers, Karaflahin et al. reported that low level of hemoglobin is associated with increase in the risk of preeclampsia. Thus, it was stressed that family planning and pre-pregnancy assessments is needed to reduce the adverse effects.[17] Patra et al. also concluded that low levels of hemoglobin in the early pregnancy is associated with preeclampsia and eclampsia and declared that low intervals between pregnancies and low nutritional supports lead to low levels of hemoglobin and adverse pregnancy complications, particularly in multiparous women.[18] Although the reason for the relationship of low levels of hemoglobin with complications such as preeclampsia is still completely unknown, factors such as lack of other nutrients in people with low level of hemoglobin,[19] intensification of oxidative stress,[20] endothelial malfunction, mediation of inflammatory responses and insulin function are among the proposed reasons which need further investigations. [21] This can be due to the lower socio-economic status of these women.

In this study, it became clear that the significant inverse relationship between hematocrit in the second half and birth weight and height was overshadowed by gestational age and in fact gestational age is the most important variable associated with hematocrit values. The indices of birth weight, height and head circumference are also influenced by gestational age more than other variables (p < 0.001). The significant inverse relationship between the hematocrits in the two halves of pregnancy and gestational age can be noted as one of the other results obtained in this study. Accordingly, by increase in gestational age, hematocrit decreased and physiological dilution of blood became more visible. Through the progress of normal pregnancy, red cell mass will increase 25% and plasma volume will increase 40% which increases uterine placental blood flow through the decrease in blood hematocrit and viscosity as well as peripheral resistance. [8] On the other hand, need for iron is increased during the second half of pregnancy (an average of 6–7 mg per day) which in turn reduces the concentration of the mothers’ hemoglobin and hematocrit.[22]

The main reason for the increased hemoglobin and hematocrit levels in the second half of pregnancy in various studies[16,22–24] was blood concentration or in the other words, lack of physiological dilution of blood in the pregnant mothers. Thus, changes in hemoglobin and hematocrit values in the two halves of pregnancy were determined for the subjects through studying the difference between hemoglobin and hematocrit in the second half of pregnancy compared to the first half of pregnancy[16] and the relationship between the obtained variables and pregnancy outcome was analyzed. In this study, the difference between hematocrits in the two halves of pregnancy was significantly correlated with the risk of preeclampsia so that in patients with preeclampsia, hematocrit in the second half reduced less than other mothers. Von Tempelhoff et al. also showed that lack of decrease in hematocrit during the second half of pregnancy compared to the first half was significantly correlated to the risk of preeclampsia.[24] Chang et al. also showed the relationship between hematocrit values above 44 percent in the third trimester and adverse perinatal outcome in women with preeclampsia.[25] In his study, Steer also showed that the hemoglobin levels above 12 g/dL at the late second trimester were associated with three times increase in the risk of preeclampsia.[26] Hematocrit values equal with or greater than 40 percent are because of the increase in the number of red blood cells or more likely, lack of physiological increase in plasma volume.[10] Blood concentration is one of the main symptoms of preeclampsia and is probably caused by generalized vasoconstriction and endothelial dysfunction associated with increased vascular permeability. Depending on the disease severity, blood concentration increases with preeclampsia, while in women with pregnancy induced hypertension, blood volume is usually normal. [7] It seems that the significant relationship of the difference between hematocrit in the two halves of pregnancy with preeclampsia development was caused by blood concentration in this study.

Using multivariate regression analysis, it was shown that the relationship between gestational age and the difference between hematocrit in the two halves of pregnancy was stronger. Amburgey et al. also suggested that the strong relationship between hemoglobin level and gestational age in women with preeclampsia and less gestational age is probably because of higher blood concentration in these women compared to women with preeclampsia but more gestational age.[16] Generally, according to the results of this study, it can be concluded that gestational age is the main factor associated with the hematocrit values, so that increase in gestational age leads to decrease in hematocrit. However, although the relationship between the two variables was not significant in this study and with this sample size, it seems that hemoglobin also decrease with increase of gestational age. Nevertheless, hematocrit is a parameter with more accuracy.

In conclusion, one of the results obtained in this study was the significant relationship of the difference between hematocrit in the two halves of pregnancy with preeclampsia. Therefore, lack of decrease in hematocrit in the second half in those with preeclampsia or those who are going to show signs and symptoms of preeclampsia within the next weeks, can have clinical application. In addition, the significant relationship between low levels of hemoglobin in the first half of pregnancy and preeclampsia as well as the significant relationship between low levels of hemoglobin in the second half of pregnancy and risk of preterm premature rupture of membranes might be useful to identify the women at risk of these complications and to perform the preventive measures.

Research Article of Isfahan University of Medical
Sciences, No: 186060

Source of Support: Isfahan University of Medical Sciences

Conflict of Interest: None declared.

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